2-substituted-indole-1-lower-alkanecarboxamides having anti-secretory or anti-ulcer activity

ABSTRACT

2-Substituted-indole-1-lower-alkanecarboxamides, prepared by amidation of the corresponding acid or ester; by hydrolysis or thiohydrolysis of the corresponding carbonitrile; by alkylation of a suitable indole with a halo-lower-alkanecarboxamide; or by hydrolysis of a 1-indolechlorosulfonylcarbamyl derivative, have anti-secretory and anti-ulcer activities.

RELATED APPLICATIONS

This is a division of my prior, copending application Ser. No. 624,334,filed Oct. 21, 1975, now U.S. Pat. No. 4,021,448, patented May 3, 1977.

BACKGROUND OF THE INVENTION

a. Field of the Invention

This invention relates to2-substituted-indole-1-lower-alkanecarboxamides useful as anti-secretoryand anti-ulcer agents.

B. Description of the Prior Art

The compound 3-methyl-1-indoleacetamide, unsubstituted in the 2-positionof the indole nucleus, is described by Swaminathan et al., J. Org. Chem.22, 70-72 (1957), but no utility is suggested for the compound.

SUMMARY OF THE INVENTION

This invention relates, in one composition of matter aspect, to 2-R₂-3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamides, having usefulanti-secretory and anti-ulcer activities, where R₂, R₃ and R₅ haveparticular meanings more specifically described hereinbelow.

The invention also relates, in a second composition of matter aspect, to2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamides having a formylgroup in either the 2- or 3-positions of the indole nucleus which areuseful as intermediates for preparing the corresponding compounds havinga hydroxymethyl in either the 2- or 3-positions.

The invention also relates, in a method aspect, to a method of reducinggastric secretion and incidence of ulcer formation in humans comprisingadministering an effective anti-secretory/anti-ulcer amount of a 2-R₂-3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamide.

In one process aspect, the invention relates to a process for preparinga 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamide comprising reactinga mixed anhydride of a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanoic acidwith an amine.

In another process aspect, the invention relates to a process forpreparing a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamidecomprising reacting an acid halide of a 2-R₂ -3-R₃ -5-R₅-1-indole-lower-alkanoic acid with an amine.

In another process aspect, the invention relates to a process forpreparing a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamidecomprising reacting a lower-alkyl 2-R₂ -3-R₃ -5-R₅-1-indole-lower-alkanoate with an amine.

In another process aspect, the invention relates to a process forpreparing a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamidecomprising hydrolyzing a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanonitrile.

In another process aspect, the invention relates to a process forpreparing a 2-R₂ -3-R₃ -5-R₅ -1-indole-carboxamide comprisinghydrolyzing a 2-R₂ -3-R₃ -5-R₅ -1-halo-sulfonylcarbamylindole.

In another process aspect, the invention relates to a process forpreparing a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanethiocarboxamidecomprising reacting a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanonitrilewith hydrogen sulfide in the presence of an alkali metal alkoxide.

In another process aspect, the invention relates to a process forpreparing a 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanecarboxamide whereinR₂ is hydroxymethyl and R₃ is hydroxymethyl or2,2,2-trifluoro-1-hydroxyethyl comprising reducing with an alkali metalborohydride or with hydrogen over a palladium-on-charcoal catalyst acorresponding compound where R₂ or R₃ are, respectively, formyl ortrifluoroacetyl.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, this invention relates to 2-R₂ -3-R₃ -5-R₅-1-indole-lower-alkanecarboxamides having useful anti-secretory andanti-ulcer activities and having the formula: ##STR1## where R' ishydrogen or methyl; R" is hydrogen, methyl or (CH₂)_(m) OH, where m is 0(zero), 2 or 3; R₁ is hydrogen or methyl; R₂ is methyl, ethyl, phenyl orhydroxymethyl; R₃ is methyl, ethyl, hydroxymethyl, trifluoroacetyl or2,2,2-trifluoro-1-hydroxyethyl; R₅ is hydrogen, chlorine or fluorine; Xis O or S; and n is 0 (zero), 1, 2 or 3, n being 0 only when R₅ ischlorine.

Also within the ambit of the invention are certain compounds of theabove formula I where either R₂ or R₃, instead of representinghydroxymethyl, represents formyl (CHO), the other values of R₂ and R₃being the same as given above exclusive of hydroxymethyl. Theformyl-substituted compounds are either inactive or only marginallyactive as anti-secretory or anti-ulcer agents but are useful asintermediates for the preparation of the corresponding compounds wherethe formyl group is reduced to the corresponding hydroxymethyl group. Aparticularly preferred group of compounds of this latter type are thosewherein R', R" and R₁ are each hydrogen; R₂ is methyl or phenyl and R₃is formyl, or R₂ is formyl and R₃ is methyl; R₅ is hydrogen or fluorine;X is 0; and n is 1, 2 or 3.

The compounds of formula I are prepared by one of several methodsinvolving amidation of the corresponding acid or ester; hydrolysis orthiohydrolysis of the corresponding carbonitrile; alkylation of anappropriate indole with a halo-lower-alkanecarboxamide in the presenceof a strong base; or by hydrolysis of an N-chlorosulfonylcarbamylderivative.

Thus, amidation of the corresponding carboxylic acid to produce thecompounds of formula I were X is 0 comprises reacting the acid with alower-alkyl halo-formate in the presence of an acid acceptor, andreacting the resulting mixed anhydride, without isolation, with anappropriate amine as represented by the reaction sequence: ##STR2##where R', R", R₁, R₂, R₃, R₅ and n have the meanings given above, Halrepresents halogen, and R'" represents lower-alkyl. The reaction iscarried out at a temperature in the range from -10° to about 30° C. andin an inert organic solvent, for example chloroform, methylenedichloride, ethylene dichloride, benzene, toluene or diethyl ether.

Alternatively, the carboxylic acid can be converted to the correspondingacid halide by reacting the former with a thionyl halide or a phosphoruspentahalide, and reacting the resulting acid halide with an appropriateamine as before to give the compounds of formula I where X is O.

The procedure involving amidation of the ester to produce the compoundsof formula I where X is O comprises heating a mixture of the ester andan appropriate amine, either with or without a solvent, at a temperaturefrom 90° to about 150° C. as represented by the equation: ##STR3## whereR', R", R'", R₁, R₂, R₃, R₅ and n have the meanings given above.

The compounds of formula I where X is O and R' and R" are each hydrogenare prepared by hydrolysis of the corresponding lower-alkanonitriles offormula V. The reaction is carried out by heating a solution of thecarbonitrile in 90% aqueous sulfuric acid at a temperature in the rangefrom 0° to 100° C. and is represented by the equation: ##STR4## whereR₁, R₂, R₃, R₅ and n have the meanings given above.

The compounds of formula I where X is O, R' and R" are both hydrogen,and n is zero are prepared by reaction of an appropriate1-unsubstituted-2-R₂ -3-R₃ -5-R₅ -indole of formula VI with ahalo-sulfonylisocyanate followed by hydrolysis of the resulting1-halo-sulfonylcarbamylindole of formula VII. The method is representedby the reaction sequence: ##STR5## where R₂, R₃, R₅ and Hal have themeanings given above.

The compounds of formula I where X is S are prepared by reaction of thecorresponding lower-alkanonitriles of formula V with hydrogen sulfide inthe presence of an alkali metal alkoxide. The reaction is preferablycarried out by dissolving the nitrile in a solution of the alkoxide inexcess lower-alkanol, saturating the resulting solution with hydrogensulfide, and heating the solution in a pressure flask.

Finally, the compounds of formula I where R₂ or R₃ are hydroxymethyl orwhere R₃ is 2,2,2-trifluoro-l-hydroxyethyl are prepared by reducing thecorresponding compound where R₂ or R₃ is formyl or where R₃ istrifluoroacetyl with an alkali metal borohydride or with hydrogen over apalladium-on-charcoal catalyst. Reduction with an alkali metalborohydride is advantageously carried out in a lower-alkanol solvent ata temperature in the range from 0° to 60° C., while catalytic reductionis carried out in a lower-alkanol solvent at a temperature from 20° to50° C. and at hydrogen pressures of from 50 to 100 p.s.i.

The compounds of formulas II, IV, V and VI are generally known classesof compounds, and many examples are known in the art, although certainnovel species of these compounds are required to prepare the compoundsof the invention represented by formula I. The novel species areprepared by conventional methods well-known in the art.

Thus, the 2-R₂ -3-R₃ -5-R₅ -indoles of formula VI are prepared using theFisher indole synthesis which comprises reacting a 4-R₅ -phenylhydrazinewith an appropriate ketone having the formula: ##STR6## where R₂, R₃ andR₅ have the meanings given above.

The 2-R₂ -3-R₃ -5-R₅ -l-indole-lower-alkanonitriles of formula V areprepared either by reaction of an appropriate 1-unsubstituted-indole offormula VI with an appropriate acrylonitrile in the presence of a strongbase (to prepare the compounds where n is 2) or by reaction of a1-unsubstituted-indole of formula VI with a halo-lower-alkanonitrile inthe presence of a strong base such as an alkali metal hydride.

The esters of formula IV are prepared either by esterification of thecorresponding carboxylic acids of formula II by conventional proceduresor by reaction of a 1-unsubstituted-indole of formula VI with alower-alkyl halo-lower-alkanoate in the presence of a strong base, forexample an alkali metal hydride.

The 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanoic acids of formula II areprepared by saponification of the corresponding esters which areprepared as described above.

In standard biological test procedures, described generally by Shay etal., Gastroenterology 5, 43 (1945) and 26, 906 (1954) and by Selmici etal., Acta Physiol. Acad. Sci. Hung. 25 (1), 101-104 (1964); C.A. 62,2130b (1965), the compounds of formula I have been found to possessanti-secretory and anti-ulcer activities and are thus useful asanti-secretory and anti-ulcer agents. Anti-secretory activity wasdetermined in male albino Wistar rats weighing approximately 180 g.using the method described by Shay et al. which is described as follows:the rats were divided into medicated groups of at least five rats eachand control groups of ten rats. The rats were medicated orally oncedaily for 2 days prior to stomach ligation and once again immediatelyfollowing ligation. All drugs were administered as the free base, andcontrol rats received only the vehicle of medication. The rats werehoused individually in wire cages, food was withdrawn 48 hours prior tosurgery, and water was withdrawn at the time of surgery. Laparotomy wasperformed under light ether anesthesia, the pyloric-duodenal junctionwas ligated, and the wound was closed with metal clips and sprayed witha protective surgical dressing. Five hours following surgery, the ratswere sacrificed, the stomach was removed, and the gastric juicecollected. The gastric fluid was centrifuged, the total volume, color,and volume of solids were recorded. The pH of the gastric fluid was thendetermined on a Beckman pH meter, and the "free" and "total"hydrochloric acid content of each gastric sample was determined bytitrating an aliquot of the gastric fluid (diluted to approximately 10ml. with distilled water) by titrating with 0.1N sodium hydroxideagainst Toepfers reagent and phenolphthalein, respectively. Bydetermining the milliequivalents of hydrochloric acid per milliliter ofgastric juice and knowing the total volume of gastric juice secreted byeach rat, the total acid output can be calculated. Since pH is afunction of "free" acid, the activity of the test compounds can beevaluated by comparison of the mean "free" acid of medicated rats withthe mean "free" acid of the controls, and the activity can thus beexpressed in terms of percent inhibition of free acid.

The anti-ulcer activity of the compounds was determined using thereserpine-induced anti-ulcer test method, described by Selmici et al.,which is described briefly as follows: male, albino, Sprague-Dawleyrats, weighing approximately 300 g., were divided into medicated andcontrol groups of at least five rats each, and one positive controlgroup of five rats medicated with a known drug at the active dose wasrun with each experiment. The rats were medicated forty-eight,twenty-four, and one hour before receiving an injection of reserpine.All test drugs were administered orally in terms of base, and thecontrol rats received only the vehicle of medication. The rats werehoused individually in wire cages, and food was withdrawn 24 hours priorto injection of reserpine, while water was allowed ad libitum. One hourfollowing the third medication, 5.0 mg. of reserpine per kilogram ofbody weight in a concentration of 5 mg./ml. was injected intramuscularlyin each rat. Eighteen hours after injection the rats were sacrificed,their stomachs removed, opened along the greater curvature, rinsed inwarm saline, and pinned to a cork board for gross observation. Thestomachs were examined for the number and size of ulcerations located inthe glandular portion of the stomach with the aid of a one millimetergrid ocular with a 10x dissecting microscope. The degree of ulcerationwas arbitrarily graded according to the number and size of the ulcers asfollows:

0<1 mm.² 1 point

1<3 mm.² 2 points

≧3 mm.² 5 points.

The points were added together and divided by the number of rats in eachgroup to give an ulcer score, and the difference in the mean scores ofthe medicated and control group was expressed as percent inhibition ofulceration. Alternatively, the results can be expressed as a ratio ofthe total number of rats with any degree of ulceration (as thenumerator) to the total number of rats in the test group (as thedenominator).

The compounds of formula I were thus found to inhibit secretion ofgastric fluids and to inhibit reserpineinduced stomach ulceration whenadministered in a dose range of from around 10 mg./kg. to around 200mg./kg. These results indicate usefulness of the compounds in humans asantisecretory/anti-ulcer agents when administered at a dose of 50 mg.per patient three or four times a day either alone or as the essentialactive ingredient. The compounds are preferably administered orally.

The actual determination of the numerical biological data definitive fora particular compound of formula I is readily determined by standardtest procedures by technicians versed in pharmacological test procedureswithout the need for any extensive experimentation.

The compounds of formula I can be prepared for use by incorporation inunit dosage form as tablets or capsules for oral administration eitheralone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, sodium bicarbonate, sodium lauryl sulfate,sugar, dextrose, mannitol, cellulose, gum acacia, and the like.Alternatively, they can be formulated for oral administration in aqueousalcohol, glycol, or oil solutions or oil-water emulsions in the samemanner as conventional medicinal substances are prepared. They can alsobe formulated for oral use with foodstuffs or admixed with foodstuffsfor veterinary use.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared, ultraviolet, and NMR spectra,and confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

SPECIFIC EXEMPLARY DISCLOSURE A. Preparation of IntermediatesPreparation 1 (The 2-R₂ -3-R₃ -5-R₅ -indoles of formula VI).

A solution of 1 g. (0.008 mole) of 4-fluorophenylhydrazine in 10 ml. ofacetone was flushed with nitrogen, refluxed for ten minutes, and thentaken to dryness in vacuo to leave 1.43 g. of the expected hydrazone asa golden yellow oil.

The latter was dissolved in 90 ml. of p-cymene, the flask was flushedwith nitrogen, about 30 g. (0.22 mole) of zinc chloride was added, andthe solution was refluxed for an hour. The solvent layer was decantedand taken to dryness in vacuo leaving 20.8 g. of a brown oil which wasextracted with hexane and crystallized from the latter to give 6.7 g. of5-fluoro-2-methylindole, m.p. 97°-98° C.

The latter (4.5 g., 0.03 mole) in 3 ml. of dimethylformamide (DMF) wasadded with stirring to a solution of 3 ml. (0.03 mole) of phosphorusoxychloride in 10 ml. of DMF while maintaining the temperature between20° and 30° C. The solution was allowed to stand for two hours atambient temperature, then poured over ice, and neutralized by theaddition of a solution of 5.7 g. of sodium hydroxide in 30 ml. of water.The crystals which separated were collected, washed with water andrecrystallized from methanol to give 2.7 g. of2-methyl-3-formyl-5-fluoroindole, m.p. 217°-220° C.

Other known 2-R₂ -3-R₃ -5-R₅ -indoles of formula VI used in thepreparation of the compounds of formula I are the following:

2-Methyl-3-formylindole disclosed by Beswas et al., Tetrahedron, 24 (3),1145-1162 (1968);

2,3-Dimethyl-5-chloroindole disclosed by Rothstein et al., Compt. rend.242, 1042-1043 (1956);

2-Ethyl-3-methylindole disclosed by Lesiak, Roczniki Chem. 36, 1097-1100(1962); C.A. 58, 5615h (1963);

2-Methyl-3-ethylindole disclosed by McLean et al., Can. J. Chem. 49(22), 3642-3647 (1971);

2-Phenyl-3-methylindole disclosed by Kanaoka et al., Chem. Pharm. Bull.(Tokyo) 14 (9), 934-939 (1966); and

2,3-Dimethylindole disclosed by VanDuuren, J. Org. Chem. 26, 2954-2960(1961).

Preparation 2 (The 2-R₂ -3-R₃ -5-R₅ -1-indole-lower-alkanoic acids offormula II).

A. To a solution of 42 g. (0.29 mole) of 2,3-dimethylindole in 700 ml.of DMF was added 11.5 g. (0.29 mole) of a 60.1% dispersion of sodiumhydride in mineral oil. The mixture was stirred at ambient temperaturefor one hour, cooled to 0° C. and then treated dropwise with stirringover a fifteen minute period with ethyl bromoacetate. The cooling bathwas then removed, the mixture was stirred for two hours at roomtemperature, then poured into 2.5 liters of ice/water. The solid whichseparated was collected, washed with water, dissolved in 200 ml. of hotmethanol and the solution treated with a solution of 30 g. of potassiumhydroxide in 100 ml. of water. The resulting solution was refluxed forabout two minutes, cooled, diluted to about 1600 ml. with water,filtered, and the filtrate acidified by the addition of concentratedhydrochloric acid to pH 2. The solid which separated was collected andrecrystallized from benzene to give 9 g. of 2,3-dimethyl-1 -indoleaceticacid, m.p. 186°-188° C.

B. A mixture of 4.5 g. (0.019 mole) ofγ-(2-methyl-3-formyl-1-indole)butyramide (see Example 4J below), 3.5 g.(0.063 mole) of potassium hydroxide and 3 ml. of 85% aqueous hydrazinehydrate in 30 ml. of triethylene glycol was refluxed with stirring undera nitrogen atmosphere for three hours. The condenser was then removeduntil the temperature of the solution was raised to 200° C., thecondenser was then replaced and the mixture heated for an additional 6hours with stirring at 200° C. The resulting thick slurry was dilutedwith 30 ml. of water and acidified with dilute hydrochloric acid. Thered solid which separated was filtered, washed with water andrecrystallized from carbon tetrachloride to give 2.9 g. ofγ-(2,3-dimethyl-1-indole)butyric acid, m.p. 102°-104° C.

C. To a stirred suspension of 27.0 g. of a 56% mineral oil dispersion ofsodium hydride in 300 ml. of DMF was added, with cooling and stirring, asolution of 95.6 g. (0.6 mole) of 2-ethyl-3-methylindole in 300 ml. ofDMF. The solution was stirred at room temperature for 1 hour, thencooled to -15° C. and treated with 72.3 ml. (0.65 mole) of ethylbromoacetate. The product was isolated and saponified with 60 g. ofpotassium hydroxide in 500 ml. of methanol using the procedure describedin Preparation 2A to give 87 g. of 2-ethyl-3-methyl-1-indoleacetic acid.

Also useful in the preparation of the compounds of formula I is theknown compound β-(2,3-dimethyl-1-indole)-propionic acid disclosed byAlmond et al., J. Chem. Soc. 1870-1874 (1952).

Preparation 3 (The lower-alkyl 2-R₂ -3-R₃ -5-R₅-1-indole-lower-alkanoates of formula IV)

A. A solution of 50 g. (0.25 mole) of 2,3-dimethyl-1-indoleacetic acidin 250 ml. of absolute methanol was saturated with anhydrous hydrogenchloride and then refluxed for three hours. The solution was then takento dryness, the residue partitioned between water and ethyl acetate, andthe organic layer washed once with dilute sodium hydroxide, once withbrine and then taken to dryness. The residual yellow brown solid wasrecrystallized twice from methanol to give 25 g. of methyl2,3-dimethyl-1-indoleacetate, m.p. 88°-90° C.

B. Using a procedure similar to that described in Preparation 2, 143.3g. (0.9 mole) of 2-methyl-3-ethylindole was alkylated with 150 g. (0.98mole) of methyl bromoacetate in the presence of 40.5 g. (0.96 mole) of a57% mineral oil dispersion of sodium hydride in 450 ml. of DMF. Theproduct was isolated in the form of the ester which was recrystallizedfrom chloroform/hexane to give two crops, 90 g., m.p. 91°-92° C. and 11g., m.p. 88°-90° C., of methyl 2-methyl-3-ethyl-1-indoleacetate.

C. A solution of 99.3 g. (0.4 mole) ofβ-(2,3-dimethyl-1-indole)propionitrile (German Pat. No. 641597,published Feb. 11, 1937) in 200 ml. of methanol was cooled to -15° C.and saturated with anhydrous hydrogen chloride for about one hour. Thesolution was then refluxed for one half hour, allowed to standovernight, and then poured onto ice and the mixture extracted withchloroform. The organic extracts were washed with aqueous sodiumbicarbonate, dried over magnesium sulfate and concentrated to dryness togive 81 g. of crude material which was distilled in vacuo to give 78.5g. of methyl β-(2,3-dimethyl-1-indole)propionate, b.p. 151°-158°C./0.4-0.7 mm., n_(D) ²⁵.5 1.5663.

Preparation 4 (The 2-R₂ -3-R₃ -5-R₅ -1-indole)-lower-alkanonitriles offormula V)

A. A solution of 72 g. (0.4 mole) of 5-chloro-2,3-dimethylindole in 400ml. of dioxane was treated with 28 ml. of acrylonitrile (0.43 mole), and22.8 ml. of a 35% solution of benzyltrimethylammonium hydroxide inmethanol was added and the solution allowed to stand for 2 days. Thereaction mixture was poured into 1 liter of water and ice, neutralizedwith 30 ml. of concentrated hydrochloric acid, and the solid whichseparated was collected and recrystallized from isopropanol to give 78g. of β-(5-chloro-2,3-dimethyl-1-indole)-propionitrile, m.p. 86°-88° C.

Other compounds of formula V similarly prepared were the following:

B. β-(2,3-Dimethyl-5-fluoro-1-indole)propionitrile (30 g., m.p. 85°-86°C. from isopropanol) prepared by reaction of 32.64 g. (0.2 mole) of2,3-dimethyl-5-fluoroindole with 14 ml. of acrylonitrile in 200 ml. ofdioxane in the presence of 11.4 ml. of 35% benzyltrimethylammoniumhydroxide;

C. β-(2-Ethyl-3-methyl-1-indole)propionitrile (123.6 g.) prepared byreaction of 95.6 g. (0.6 mole) of 2-ethyl-3-methylindole with 42 ml.(0.64 mole) of acrylonitrile in 600 ml. of dioxane in the presence of34.2 ml. of 35% benzyltrimethylammonium hydroxide;

D. β-(2-Methyl-3-ethyl-1-indole)propionitrile (114 g.) prepared byreaction of 95.6 g. (0.6 mole) of 2-methyl-3-ethylindole with 42 ml.(0.6 mole) of acrylonitrile in 600 ml. of dioxane in the presence of34.2 ml. of 35% benzyltrimethylammonium hydroxide;

E. β-(2-Methyl-3-formyl-1-indole)propionitrile (51 g., m.p. 149°-150°C., from methylene dichloride) prepared by reaction of 69.2 g. (0.44mole) of 2-methyl-3-formylindole with 30.5 ml. (0.46 mole) ofacrylonitrile in 435 ml. of dioxane in the presence of 21.8 ml. of 35%benzyltrimethylammonium hydroxide;

F. β-(2-Phenyl-3-methyl-1-indole)propionitrile (17.7 g., m.p. 85°-87°C., from benzene/cyclohexane) prepared by reaction of 30 g. (0.15 mole)of 2-phenyl-3-methylindole with 11.2 ml. (0.17 mole) of acrylonitrile in80 ml. of dioxane in the presence of 3 ml. of 35%benzyltrimethylammonium hydroxide.

G. β-(2-Methyl-3-formyl-5-fluoro-1-indole)propionitrile (29.4 g., m.p.188°-190° C., from methylene dichloride) prepared by reaction of 28.2 g.(0.16 mole) of 2-methyl-3-formyl-5-fluoroindole with 18 ml. ofacrylonitrile in 250 ml. of dioxane in the presence of 3 ml. ofbenzyltrimethylammonium hydroxide.

H. β-(3-Methyl-1-indole)propionitrile (155 g., m.p. 85°-90° C., fromisopropanol) prepared by reaction of 200 g. (1.52 moles) of3-methylindole with 107 ml. of acrylonitrile in 1.2 liters of dioxane inthe presence of 88 ml. of 35% benzyltrimethylammonium hydroxide.

J. β-(2,3-Dimethyl-1-indole)-α-methylpropionitrile (30 g.) prepared byreaction of 36.3 g. (0.25 mole) of 2,5-dimethyl-indole with 17.8 g.(0.62 mole) of methacrylonitrile in 250 ml. of dioxane in the presenceof 14.5 ml. of 35% benzyltrimethylammonium hydroxide.

K. γ-(2-Methyl-3-formyl-1-indole)butyronitrile (120 g., from benzene)prepared by reaction of 113 g. (0.71 mole) of 2-methyl-3-formylindolewith 158 g. (1.07 mole) of 4-bromobutyronitrile in 1 liter of DMF in thepresence of 37.5 g. (0.89 mole) of a 57% mineral oil dispersion ofsodium hydride using the procedure described in Preparation 2A.

L. To a solution of 22.8 g. (0.12 mole) ofβ-(2-methyl-1-indole)propionitrile in a solution of 40 ml. of carbontetrachloride and 19 ml. of DMF was added 25 ml. of trifluoroaceticanhydride while maintaining the temperature at -10° C. When addition wascomplete, the mixture was allowed to stand for about an hour at ambienttemperature, then slurried with water, and the solid which had separatedwas collected and recrystallized from carbon tetrachloride to give 30.0g. of β-(2-methyl-3-trifluoroacetyl-1-indole)-propionitrile, m.p.108.5°-109.5° C.

M. To a solution of 33 ml. (0.36 mole) of phosphorus oxychloride in 96ml. of DMF at 10-20° C. was added with stirring a solution ofβ-(3-methyl-1-indole)propionitrile in 180 ml. of DMF while maintainingthe temperature at 15°-25° C. The solution was heated to 70°-75° C. forabout 15 minutes, then cooled and poured into 600 ml. of ice water. Themixture was basified by the addition of a solution of 62.4 g. of sodiumhydroxide in 360 ml. of water, and the solid which separated wascollected, washed with water and recrystallized from methanol to give51.5 g. of β-(2-formyl-3-methyl-1-indole)propionitrile.

N. A mixture of 60.5 g. (0.3 mole) of 2,3-dimethyl-1-indoleacetamide(described in Example 1A below), 120 g. (0.63 mole) of p-toluenesulfonylchloride and 630 ml. of pyridine was heated on a steam bath for an hour,cooled and then poured into 4 liters of ice water. The solid whichseparated was collected, washed with water and dried to give 49 g. of2,3-dimethyl-1-indoleacetonitrile, 84°-86° C.

Other known 1-indole-lower-alkanonitriles of formula V used in thepreparation of the final products of formula I are:

β-(2-Methyl-1-indole)propionitrile disclosed in German Pat. No. 641597,published Feb. 11, 1937 and

β-(2-Phenyl-3-formyl-1-indole)propionitrile disclosed by Blume et al.,J. Org. Chem. 10, 255-258 (1945).

B. Preparation of the Final Products EXAMPLE 1

A. To a solution of 22 g. (0.11 mole) of 2,3-dimethyl-1-indoleaceticacid and 15 ml. (0.11 mole) of triethylamine in 500 ml. of methylenedichloride at 0° C. was added 11.7 g. (0.11 mole) of ethylchloroformate. The solution was stirred at 0° C. for a half hour, andthen treated with an excess of a solution of ammonia in 300 ml. ofmethylene dichloride. The mixture was then stirred at ambienttemperature for an hour and a quarter. The reaction mixture wasextracted once with water, once with aqueous sodium bicarbonate and oncewith brine, then dried and evaporated to a volume of about 25 ml. anddiluted with 50 ml. of hot hexane. There was thus obtained 9 g. ofmaterial which was recrystallized from ethyl acetate to give 6.8 g. of2,3-dimethyl-1-indoleacetamide, m.p. 197°-199° C.

Other compounds of formula I which were prepared using a proceduresimilar to that described in Example 1A are as follows:

B. 2,3-Dimethyl-1-indole-N-methylacetamide (34.3 g., m.p. 187°-190° C.,from methanol) prepared by reaction of 50 g. (0.24 mole) of2,3-dimethyl-1-indoleacetic acid with 25.7 ml. (0.27 mole) of ethylchloroformate and 37.8 ml. (0.27 mole) of triethylamine in 1 liter ofmethylene dichloride and reaction of the resulting mixed anhydride withmethylamine;

C. 2-Ethyl-3-methyl-1-indoleacetamide (16.5 g., m.p. 161°-162° C, frombenzene) prepared by reaction of 43.45 g. (0.2 mole) of2-ethyl-3-methyl-1-indoleacetic acid with 19 ml. (1.1 mole) of ethylchloroformate and 78 ml. (0.2 mole) of triethylamine in 600 ml. ofmethylene dichloride and reaction of the resulting mixed anhydride withammonia;

D. γ-(2,3-Dimethyl-1-indole)butyramide (16.3 g., m.p. 132°-134° C., fromethyl acetate) prepared by reaction of 23.1 g. (0.1 mole) ofγ-(2,3-dimethyl-1-indole)butyric acid with 13.6 g. (0.1 mole) ofisobutyl chloroformate and 14.7 ml. (0.11 mole) of triethylamine in 400ml. of chloroform and reaction of the resulting mixed anhydride withammonia.

EXAMPLE 2

To a solution of 10.85 g. (0.05 mole) ofβ-(2,3-dimethyl-1-indole)propionic acid in 250 ml. of dry ether wasadded 10.43 g. (0.50 mole) of phosphorus pentachloride, and the solutionwas stirred for a half hour at -5° C., then for an additional hour atambient temperature and poured into 200 ml. of 40% aqueous dimethylaminecontaining 200 g. of ice. After standing overnight, the organic layerwas separated, the aqueous layer was extracted with ether and thecombined ether extracts dried and concentrated to dryness to give 12 g.of a crude oil which crystallized to give 8.1 g. ofβ-(2,3-dimethyl-1-indole)-N,N-dimethylpropionamide, m.p. 73°-74° C.

EXAMPLE 3

A. A mixture of 20 g. (0.092 mole) of methyl2,3-dimethyl-1-indoleacetate and 100 ml. of ethanolamine was heated on asteam bath for 3 hours, then poured into 3 liters of water, and theresulting solid collected by filtration and recrystallized from benzeneto give 18.9 g. of 2,3-dimethyl-1-indole-N-(2-hydroxyethyl)acetamide,m.p. 156°-158° C.

Other compounds of formula I which were prepared using a proceduresimilar to that described in Example 3A are as follows:

B. 2,3-Dimethyl-1-indoleacetohydroxamic acid (12.1 g., m.p. 168° C.,dec., from acetonitrile) prepared by reaction of 21.7 g. (0.1 mole) ofmethyl 2,3-dimethyl-1-indoleacetate with 14.2 g. (0.2 mole) ofhydroxylamine hydrochloride in 75 ml. of methanol in the presence of asolution of 17 g. (0.3 mole) of potassium hydroxide in 45 ml. ofmethanol;

C. 2-Methyl-3-ethyl-1-indoleacetamide (10.1 g., m.p. 168°-169° C., fromethanol) prepared by reaction of 40 g. (0.17 mole) of methyl2-methyl-3-ethyl-1-indoleacetate with 700 ml. of a saturated solution ofammonia in ethanol;

D. β-(2,3-Dimethyl-1-indole)-N-(2-hydroxyethyl)propionamide (20.8 g.,m.p. 89°-90° C., from benzene) prepared by reaction of 20.8 g. (0.09mole) of methyl β-(2,3-dimethyl-1-indole)-propionate with 100 ml. ofethanolamine;

E. β-(2,3-Dimethyl-1-indole)-N-(3-hydroxypropyl)propionamide (19.2 g.,m.p. 89°-90° C., from benzene) prepared by reaction of 20.8 g. (0.09mole) of methyl β-(2,3-dimethyl-1-indole)-propionate with 70 ml. of3-hydroxypropylamine;

F. β-(2,3-Dimethyl-1-indole)propionohydroxamic acid (22.5 g., m.p.137°-138° C., from acetonitrile) prepared by reaction of 34 g. (0.14mole) of methyl β-(2,3-dimethyl-1-indole)propionate with 20.4 g. (0.29mole) of hydroxylamine hydrochloride in 105 ml. of methanol in thepresence of 28.4 g. (0.44 mole) of potassium hydroxide in 70 ml. ofmethanol.

EXAMPLE 4

A. A solution of 10.7 g. (0.05 mole) ofβ-(2,3-dimethyl-1-indole)propionitrile in a solution of 1.5 ml. of waterand 15 ml. of concentrated sulfuric acid was heated with stirring on asteam bath for ten hours and then poured into 200 ml. of ice water andextracted with chloroform. The organic extracts were washed with diluteammonium hydroxide, then with water, dried and concentrated to drynessto give 11.5 g. of a yellow gum which was recrystallized from benzene togive 9.5 g. of β-(2,3-dimethyl-1-indole)propionamide, m.p. 106°-107° C.

Other compounds of formula I prepared using a procedure similar to thatdescribed in Example 4A are as follows:

B. β-(2,3-Dimethyl-5-chloro-1-indole)propionamide (34 g., m.p. 138°-139°C., from carbon tetrachloride) prepared by hydrolysis of 46.54 g. (0.2mole) of β-(2,3-dimethyl-5-chloro-1-indole)propionitrile in 66 ml. of90% aqueous sulfuric acid;

C. β-(2,3-Dimethyl-5-fluoro-1-indole)propionamide (9.5 g., m.p.122°-123° C., from carbon tetrachloride) prepared by hydrolysis of 29.8g. (0.18 mole) of β-(2,3-dimethyl-5-fluoro-1-indole)propionitrile in 66ml. of 90% aqueous sulfuric acid;

D. β-(2-Ethyl-3-methyl-1-indole)propionamide (29.8 g., m.p. 110°-111°C., from benzene/cyclohexane) prepared by hydrolysis of 63.69 g. (0.3mole) of β-(2-ethyl-3-methyl-1-indole)propionitrile in 88 ml. of 90%aqueous sulfuric acid;

E. β-(2-Methyl-3-ethyl-1-indole)propionamide (39 g., m.p. 90°-91° C.,from benzene/cyclohexane) prepared by hydrolysis of 63.69 g. (0.3 mole)of β-(2-methyl-3-ethyl-1-indole)-propionitrile in 88 ml. of 90% aqueoussulfuric acid;

F. β-(2-Methyl-3-formyl-1-indole)propionamide (40.1 g., m.p. 201°-202°C., from methanol) prepared by hydrolysis of 49.7 g. (0.23 mole) ofβ-(2-methyl-3-formyl-1-indole)propionitrile in a solution of 66 ml. of90% aqueous sulfuric acid;

G. β-(2-Methyl-3-formyl-5-fluoro-1-indole)propionamide (23.1 g., m.p.238°-239° C., from methanol) prepared by hydrolysis of 27.1 g. (0.12mole) of β-(2-methyl-3-formyl-5-fluoro-1-indole)propionitrile in 36 ml.of 90% aqueous sulfuric acid;

H. β-(2,3-Dimethyl-1-indole) -α-methylpropionamide (11.7 g., m.p.107.5°-110° C., from ethyl acetate/cyclohexane) prepared by hydrolysisof 30 g. (0.14 mole) of β-(2,3-dimethyl-1-indole)-α-methylpropionitrilein 55 ml. of 90% aqueous sulfuric acid;

J. γ-(2-Methyl-3-formyl-1-indole)butyramide (63.6 g., m.p. 178.5°-180°C., from ethanol) prepared by hydrolysis of 75 g. (0.33 mole) ofγ-(2-methyl-3-formyl-1-indole)-butyronitrile in 110 ml. of 90% aqueoussulfuric acid;

K. β-(2-Formyl-3-methyl-1-indole)propionamide (7.5 g., m.p. 166°-167°C., from methanol) prepared by hydrolysis of 42.5 g. (0.20 mole) ofβ-(2-formyl-3-methyl-1-indole)propionitrile in 200 ml. of 90% aqueoussulfuric acid;

L. β-(2-Methyl-3-trifluoroacetyl-1-indole)propionamide (8.3 g., m.p.158°-159° C., from methylene dichloride) prepared by hydrolysis of 20 g.(0.07 mole) of β-(2-methyl-3-trifluoroacetyl-1-indole)propionitrile in44 ml. of 90% aqueous sulfuric acid;

M. β-(2-Phenyl-3-methyl-1-indole)propionamide (5.6 g., m.p. 136°-137°C., from benzene/cyclohexane) prepared by hydrolysis of 17.7 g. (0.068mole) of β-(2-phenyl-3-methyl-1-indole)propionitrile in 21 ml. of 90%aqueous sulfuric acid;

N. β-(2-Phenyl-3-formyl-1-indole)propionamide (2.3 g., m.p. 218°-219°C., from methanol) prepared by hydrolysis of 9 g. (0.03 mole) ofβ-(2-phenyl-3-formyl-1-indole)propionitrile in 33 ml. of 90% aqueoussulfuric acid.

EXAMPLE 5

To a solution of 36 g. (0.2 mole) of 2,3-dimethyl-5-chloroindole in 300ml. of methylene dichloride was added 8 ml. of chlorosulfonylisocyanate.An additional 300 ml. of methylene dichloride was added followed by anadditional 9.3 ml. of chlorosulfonylisocyanate, and the solution wasstirred for several minutes, then diluted with 500 ml. of pentane andfiltered. The solid material was dissolved in about 300 ml. of acetone,and the solution was cooled in an ice bath and carefully diluted, withstirring, with about 20 ml. of water. When the exothermic reaction hadsubsided, another 30 ml. of water was added, the mixture was allowed tostand at ambient temperature for several minutes, then diluted with 800ml. of water and filtered. The solid material was recrystallized oncefrom methanol to give 24.7 g. of2,3-dimethyl-5-chloro-1-indolecarboxamide, m.p. 201°-203° C.

EXAMPLE 6

A solution of 95.6 g. (0.6 mole) of 2-methyl-3-formylindole in 250 ml.of DMF was added to a suspension of 28 g. (0.66 mole) of a 56% mineraloil dispersion of sodium hydride in 50 ml. of DMF, and the solution wascooled to about 20° C. and stirred for one hour. The solution was thencooled to -10° C. and treated all at once with a solution of 60 g. (0.64mole) of α-chloroacetamide in 200 ml. of DMF. The solution was allowedto warm to ambient temperature and then was heated on a steam bath for afew minutes and finally was cooled and poured into 1500 ml. of icewater. The solid which separated was collected and dried to give 112 g.of 2-methyl-3-formyl-1-indoleacetamide, m.p. 250°-252° C. A small samplerecrystallized from DMF/methanol gave material having m.p. 256-257° C.

EXAMPLE 7

A. A solution of 20 g. (0.11 mole) of 2,3-dimethyl-1-indoleacetonitrilein 100 ml. of absolute ethanol containing 200 mg. of sodium methoxidewas saturated with hydrogen sulfide, and the solution was heated in apressure flask on a steam bath for six hours and then allowed to cool toambient temperature overnight. The reaction mixture was poured into icewater and the mixture extracted with ethyl acetate. Evaporation of theorganic extracts to dryness and recrystallization of the residue fromethanol gave 18.8 g. of 2,3-dimethyl-1-indolethioacetamide, m.p.168°-171° C.

B. Following a procedure similar to that described in Example 7A, 12 g.of β-(2,3-dimethyl-1-indole)propionitrile in 100 ml. of absolute ethanolcontaining 0.3 g. of sodium methoxide was saturated with hydrogensulfide, and the solution was heated in a pressure bottle at 80° C. forsix hours. The crude product thus obtained was recrystallized fromethanol to give 4.0 g. of β(2,3-dimethyl-1-indole)thiopropionamide, m.p.119°-120° C.

EXAMPLE 8

A. A solution of 46.0 g. (0.2 mole) ofβ-(2-methyl-3-formyl-1-indole)propionamide dissolved in 3 liters ofabsolute ethanol was cooled, treated with 25.7 g. (0.6 mole) of sodiumborohydride, and the mixture heated slowly on a steam bath until allmaterial had dissolved. The solution was refluxed for a half hour,filtered, concentrated in vacuo to 600 ml. and rendered basic by theaddition of a solution of 80 ml. of 35% sodium hydroxide in 920 ml. ofwater. The material, which slowly recrystallized on seeding andscratching, was collected, washed with water and recrystallized fromethanol to give 22 g. ofβ-(2-methyl-3-hydroxymethyl-1-indole)propionamide, m.p. 155° C.

Other compounds of formula I prepared using a procedure similar to thatdescribed in Example 8A are as follows:

B. γ-(2-Methyl-3-hydroxymethyl-1-indole)butyramide (8.8 g., m.p.110°-112.5° C., from ethyl acetate) prepared by reduction of 24.4 g.(0.1 mole) of γ-(2-methyl-3-formyl-1-indole)-butyramide with 12.9 g. ofsodium borohydride in 1.5 liters of absolute ethanol;

C. 2-Methyl-3-hydroxymethyl-1-indoleacetamide (13.4 g., m.p. 181°-182°C., from methanol) prepared by reduction of 21.62 g. (0.1 mole) of2-methyl-3-formyl-1-indoleacetamide with 14.36 g. (0.3 mole) of sodiumborohydride in 1500 ml. of absolute ethanol;

D. β-(2-Phenyl-3-hydroxymethyl-1-indole)propionamide (4.22 g., m.p.141°-142° C., from ethanol) prepared by reduction of 6.7 g. (0.023 mole)of β-(2-phenyl-3-formyl-1-indole)propionamide with 3.34 g. (0.07 mole)of sodium borohydride in absolute ethanol;

E. β-(2-Methyl-3-hydroxymethyl-5-fluoro-1-indole)propionamide (8.9 g.,m.p. 157°-157.5° C., from isopropanol) prepared by reduction of 16.1 g.(0.065 mole) of β-(2-methyl-3-formyl-5-fluoro-1-indole)propionamide with7.6 g. (0.2 mole) of sodium borohydride in methanol;

F. β-[2-Methyl-3-(2-trifluoro-1-hydroxyethyl)-1-indole]-propionamide(7.8 g., m.p. 138°-140° C., from methylene dichloride) prepared byreduction of 8 g. (0.027 mole) ofβ-(2-methyl-3-trifluoroacetyl-1-indole)propionamide with 2.08 g. (0.06mole) of sodium borohydride and 6.1 g. (0.08 mole) of ammonium acetatein ethanol.

G. To a solution of 15.85 g. (0.069 mole) ofβ-(2-formyl-3-methyl-1-indole)propionamide in 1800 ml. of absoluteethanol was added 1 g. of 10% palladium-on-charcoal, and the mixture wasreduced with hydrogen at 50° C. for 12 hours under a hydrogen pressureof 400 p.s.i. The catalyst was then removed by filtration and thefiltrate taken to dryness to give a solid residue which wasrecrystallized from ethyl acetate to give 1.6 g. ofβ-(2-hydroxymethyl-3-methyl-1-indole)propionamide, m.p. 180°-181° C.

BIOLOGICAL TEST RESULTS

Data obtained on administration of the compounds of formula I in rats inthe anti-secretory and anti-ulcer tests described above are given in thetable below. Unless noted otherwise, data were obtained on oraladministration. Results in the anti-secretory activity tests are givenin terms of the pH of the gastric fluid in the test animals and thepercent inhibition of free acid, while results in the anti-ulcer testare given either in terms of the percent inhibition of ulcers or as aratio representing the number of animals with ulcers (as the numerator)to the total number of animals in the test group (as the denominator).All doses are expressed in mg./kg. For reference purposes, resultsobtained in similar tests on the known reference compound,3-methyl-1-indole-acetamide, designated "Reference", which I have foundalso has anti-secretory and anti-ulcer activities, are given forpurposes of comparison.

    ______________________________________                                                     Anti-Secretory                                                                             % Inhibition                                                                            Anti-Ulcer                                Example Dose       pH     of Free Acid                                                                            % Inhibition                              ______________________________________                                         Reference                                                                            100        2.3    62        75                                        1A      0.8        --     --         0                                                1.56       --     --        38                                                3.12       --     --        45                                                6.25       --     --        75                                                12.5       --     --        81                                                25         2.6    69        95                                                50         3.0    65        98                                                100        6.0    100       99                                                200        6.7    100       --                                        1B      6.25(i.d.) 1.4    46        --                                                50(s.c.)   --     --        93                                                100        1.8    45        91                                        1C      25         --     --        84                                                100        2.8    50        96                                        1D      0.8        --     --        38                                                1.56       --     --        38                                                6.25       1.3    14         0                                                25         1.6    38        72                                                100        6.2    100       99                                        2       25         --     --        34                                                100        4.4    93        --                                        3A      50(s.c.)   --     --        69                                                100        1.4    22        84                                        3B      100        1.4    20        99                                                100        1.8    38        --                                        3C      100        2.8    86        97                                        3D      25         --     --        48                                                100        1.2    --        --                                        3E      25         --     --        51                                                100        1.4    34        --                                        3F      50         --     --        95                                                100        1.3    34        --                                        4A      1.56       --     --        43                                                6.25       --     --        48                                                25         --     --        93                                                50(s.c.)   --     --        89                                                100        5.3    100       --                                        4B      25         --     --        95                                                100        3.6    88        --                                        4C      25         --     --        94                                                100        5.9    97        --                                        4D      100        4.1    88        97                                        4E      6.25       --     --        60                                                12.5       --     --        72                                                25         --     --80                                                        50         --     --        94                                                100        3.4    42        93                                        4F      100        1.2    0          9                                        4G      100        1.1    17        5/5                                               100(s.c.)  1.2    36        --                                        4H      100        5.7    100       89                                        4J      100        1.2    17        26                                        4K      100        1.16   --        3/5                                               100(i.p.)  2.30   54        --                                                100(i.d.)  1.54   37        --                                        4L      100        1.8    46        --                                                100(i.p.)  3.8    78        --                                                100(i.d.)  2.5    65        --                                        4M      100        1.1    20        0/5                                               100(i.d.)  1.2    34        --                                                100(i.p.)  1.7    43        --                                        4N      100        1.0    0         5/5                                               100(s.c.)  1.0    0         --                                        5       25         --     --         0                                                100        2.0    41        --                                        6       100        1.1    0          0                                        7A      25         --     --        75                                                100        2.3    58        --                                        7B      100        2.2    60        100                                       8A      100        1.9    69        56                                                100(i.d.)  5.6    100                                                         100(s.c.)  6.7    100                                                         100(i.p.)  7.0    100                                                 8B      100        1.3    5          0                                                100(i.d.)  1.2    5                                                           100(s.c.)  1.2    12                                                          100(i.p.)  2.4    62                                                  8C      50(s.c.)   --     --        0/5                                               100        1.5    62        --                                                100(s.c.)  6.9    100       --                                                100(i.d.)  1.1    30        --                                                100(i.p.)  2.0    61        --                                        8D      100        1.5    28        0/5                                               100(s.c.)  1.4    38        --                                        8E      50(s.c.)   --     --        1/3                                               100        1.1    22        --                                                100(s.c.)  6.1    100       --                                                100(i.p.)  5.9    100       --                                                100(i.d.)  3.5    89        --                                        8F      50         --     --        45                                                100        1.0    2         --                                                100(s.c.)  1.0    7         --                                                100(i.p.)  1.2    24        --                                                100(i.d.)  1.5    69        --                                        8G      100        1.3    22        3/5                                               100(i.p.)  1.7    34        --                                                100(i.d.)  1.4    33        --                                        ______________________________________                                    

I claim:
 1. A method of reducing gastric secretion and incidence ofulcer formation in humans comprising orally administering thereto aneffective anti-secretory or anti-ulcer amount of a 2-R₂ -3-R₃ -5-R₅-1-indole-lower-alkanecarboxamide having the formula: ##STR7## where R'is hydrogen or methyl; R" is hydrogen, methyl or (CH₂)_(m) OH, where mis 0, 2 or 3; R₁ is hydrogen or methyl; R₂ is methyl, ethyl, phenyl orhydroxymethyl; R₃ is methyl, ethyl, hydroxymethyl, trifluoroacetyl or2,2,2-trifluoro-1hydroxyethyl; R₅ is hydrogen, chlorine or fluorine; Xis O or S; and n is 0, 1, 2 or 3, n being 0 only when R₅ is chlorine.